CN107698554A - A kind of preparation method of non-steroidal antiphlogiston tiaprofenic acid - Google Patents
A kind of preparation method of non-steroidal antiphlogiston tiaprofenic acid Download PDFInfo
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- CN107698554A CN107698554A CN201710954808.7A CN201710954808A CN107698554A CN 107698554 A CN107698554 A CN 107698554A CN 201710954808 A CN201710954808 A CN 201710954808A CN 107698554 A CN107698554 A CN 107698554A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The present invention relates to a kind of preparation method of non-steroidal antiphlogiston tiaprofenic acid; using 2 chloromethyl thiophenes as initiation material, the acetonitrile of synthesizing thiofuran 2 is reacted with third level natural division, is then methylated with dimethyl carbonate; cyan-hydrolysis, finally prepare Tiaprofenic Acid with chlorobenzoyl chloride F-K reaction.The advantage of the invention is that：The preparation method of non-steroidal antiphlogiston tiaprofenic acid of the present invention, rare, valuable and dangerous raw material is replaced with the raw material of conventional low cost and safety, avoids serious pollution problem, while greatly reduce production cost；In addition, process route of the present invention is simple, reaction time is short, stable reaction conditions, high income, and up to more than 90%, and the product purity obtained after reacting is high, and purity is up to more than 99%, therefore the present invention is applied to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical formulating art, more particularly to a kind of preparation method of non-steroidal antiphlogiston tiaprofenic acid.
Background technology
Tiaprofenic Acid (tiaprofenic acid), the entitled 5- benzoyls-alpha-methyl-2-thiophene acetic acid of chemistry, be by
The non-steroidal anti-inflammatory analgesics of French Sanofi-Aventis companies research and development, in multinational listing.This product is compared with Diclofenac, Yin
The U.S. pungent synthesis that can more effectively suppress prostaglandin of diindyl, easing pain and diminishing inflammation effect are better than brufen, and adverse reaction is few.Clinic cures mainly
Acute rheumatic arthritis, anchylosis, locomotive organ inflammation or non-inflammatory pain, postoperative pain and strain and other soft
Lesion tissue etc..
The synthetic route of Tiaprofenic Acid at present, being summed up mainly has four：
(1) Publication No. CN101177423 A Chinese patent literature discloses a kind of non-steroidal antiphlogiston tiaprofenic acid
Synthetic method, using thiophene as raw material, acylation reaction generation benzoyl ketone, then the catalysis in manganic are first carried out with chlorobenzoyl chloride
Under, one-electron oxidation reaction occurs for methyl-malonic ester, generates corresponding free radical, and then free radical occurs with thiphene ring
Free radical substitution reaction introduces more carbonyl functional groups on ring, generates corresponding substituent, obtained substitution product hydrolysis, decarboxylation
Obtain target product Tiaprofenic Acid.But the route shelved in atmosphere using manganic as catalyst the time length it is apt to deteriorate,
Catalytic effect is bad, and second step reaction is very incomplete, and catalyst amount is big, and route gross production rate is less than 10%.Reaction equation is as follows
It is shown：
(2) scientific and technical literature《The synthesis of Tiaprofenic Acid》(Zheng Gengxiu, Ji Yaowu, Huang Zhixin, [J] Chinese Medicine magazine,
1991,22(3):A kind of synthetic method of Tiaprofenic Acid 97-97) is disclosed, is raw material with thiophene, is first generated with acetic anhydride
Acetyl thiophene, then react to obtain rearrangement product Alpha-Methyl 2- thiophene acetic acids, Friedel- with the Darzens of acetyl thiophene
Crafts is acylated to obtain target product.The step oxidation reaction yield of this method the 4th is very low, and gross production rate is less than 10%, reacts into
This height is not suitable for industrialized production.It is difficult to purify due to benzoic acid impurity be present in obtained product.Reaction equation is as follows：
(3) scientific and technical literature《The synthesis of Tiaprofenic Acid》(Sun Min, Cai Jin, all texts etc., [J] Chinese Journal of Pharmaceuticals,
2006,37(12):A kind of synthetic method of Tiaprofenic Acid 796-797) is disclosed, is raw material with thiophene, is obtained with propionic acid anhydride reactant
To 2- propiono thiophene, this step yield is more than 90%, but committed step second step uses iodine and triethyl orthoformate as raw material,
Rearrangement product alpha-methyl-2-thiophene acetic acid ethyl ester is obtained under the effect of catalyst cuprous oxide, hydrolysis obtains corresponding acid, finally
Target product is obtained with chlorobenzoyl chloride F-K reaction.This method second step uses cuprous oxide to be imitated as catalyst
Rate is very low, and still incomplete using substantial amounts of Iod R.In addition, it is difficult to remove due to benzoic acid be present in the product that reaction obtains
To the greatest extent, product quality is influenceed, the route total recovery is less than 30%, and industrialized production has extremely difficult.Specific synthetic route is as follows：
(4) scientific literature Journal of Chemical Research, 37 (7), 2013,406-408 disclose one kind
The synthetic method of Tiaprofenic Acid, using thiophene as initiation material, through acylation, bromo, carbonyl-protection, reset, hydrolysis, most afterwards through paying gram
It is acylated to be made.Program synthetic route is grown, and reagent is more expensive, and cost is higher.Specific synthetic route is as follows：
In summary, Tiaprofenic Acid is prepared according to literature method and following defect is present：Reaction yield is low, or environmental pollution
Greatly, or severe reaction conditions, or reaction cost height etc., therefore it is not used to industrialized production.
The content of the invention
The present invention is low or big for environment pollution for reaction yield, or severe reaction conditions, or reaction cost height etc. is asked
A kind of topic, it is proposed that preparation method of non-steroidal antiphlogiston tiaprofenic acid.
In order to solve the above technical problems, the technical scheme is that：A kind of preparation of non-steroidal antiphlogiston tiaprofenic acid
Method, its innovative point are：Using 2- chloromethyl thiophenes as initiation material, synthesizing thiofuran -2- acetonitriles are reacted with third level natural division, so
Methylated afterwards with dimethyl carbonate, cyan-hydrolysis, finally prepare Tiaprofenic Acid with chlorobenzoyl chloride F-K reaction；Tool
Body comprises the following steps：
(1) preparation of thiophene -2- acetonitriles (I)：Using 2- chloromethyl thiophenes and third level natural division as raw material, in polar solvent
In, reaction in the basic conditions prepares thiophene -2- acetonitriles (I)；Specific reaction is as follows：
(2) preparation of 2- thienyls propionitrile (II)：Using thiophene -2- acetonitriles and dimethyl carbonate as raw material, with alkali with mutually turn
Shifting catalyst catalysis prepares 2- thienyls propionitrile (II)；Specific reaction is as follows：
(3) preparation of 2- thienyls propionic acid (III)：Using glacial acetic acid as solvent, the hydrolysis preparation 2- thiophenes under the conditions of dilute sulfuric acid
Fen base propionic acid (III)；Specific reaction is as follows：
(4) preparation of Tiaprofenic Acid (IV)：Using 2- thienyls propionic acid and chlorobenzoyl chloride as raw material, under Louis acid catalysis
Tiaprofenic Acid (IV) is prepared through F-K reaction；Specific reaction is as follows：
Further, in the step (1), polar solvent selection acetonitrile, alkali selection potassium carbonate, reaction temperature 60-70
℃。
Further, in the step (2), alkali selection potassium carbonate, phase transfer catalyst selection TBAB, reaction
Temperature is 120-130 DEG C.
Further, in the step (3), dilute sulfuric acid is from the dilute sulfuric acid that mass percentage concentration is 49%, reaction temperature
For 120-130 DEG C.
Further, in the step (4), lewis acid is zinc acetate, and reaction temperature is room temperature.
The advantage of the invention is that：The preparation method of non-steroidal antiphlogiston tiaprofenic acid of the present invention, with conventional low cost and peace
Full raw material replaces rare, valuable and dangerous raw material, avoids serious pollution problem, while greatly reduce and be produced into
This；In addition, process route of the present invention is simple, reaction time is short, stable reaction conditions, high income, up to 90% with
On, and the product purity obtained after reacting is high, purity is up to more than 99%, therefore the present invention is applied to industrialized production.
Embodiment
The following examples can make professional and technical personnel that the present invention be more fully understood, but therefore not send out this
It is bright to be limited among described scope of embodiments.
The preparation method of non-steroidal antiphlogiston tiaprofenic acid of the present invention, using 2- chloromethyl thiophenes as initiation material, with front three
Base silicon cyanogen reacts synthesizing thiofuran -2- acetonitriles, is then methylated with dimethyl carbonate, cyan-hydrolysis, finally and chlorobenzoyl chloride
F-K reaction prepares Tiaprofenic Acid；Specifically comprise the following steps：
(1) preparation of thiophene -2- acetonitriles (I)：Using 2- chloromethyl thiophenes and third level natural division as raw material, in acetonitrile,
Reaction prepares thiophene -2- acetonitriles (I) under conditions of potassium carbonate and 60-70 DEG C；Specific reaction is as follows：
(2) preparation of 2- thienyls propionitrile (II)：Using thiophene -2- acetonitriles and dimethyl carbonate as raw material, with carbonic acid diformazan
Ester itself is solvent, and 2- thienyl propionitrile is prepared under the conditions of potassium carbonate and TBAB catalysis and 120-130 DEG C
(II)；Specific reaction is as follows：
(3) preparation of 2- thienyls propionic acid (III)：Using glacial acetic acid as solvent, in dilute sulphur that mass percentage concentration is 49%
Under the conditions of acid, and hydrolysis prepares 2- thienyls propionic acid (III) under the conditions of 120-130 DEG C；Specific reaction is as follows：
(4) preparation of Tiaprofenic Acid (IV)：Using 2- thienyls propionic acid and chlorobenzoyl chloride as raw material, under condition of no solvent,
Tiaprofenic Acid (IV) is prepared under zinc acetate catalysis and under room temperature condition through F-K reaction；Specific reaction is as follows：
Preparation method below by specific embodiment to non-steroidal antiphlogiston tiaprofenic acid of the present invention, carry out specifically
It is bright：
The preparation of the thiophene -2- acetonitriles (I) of embodiment 1
2- chloromethyl thiophene 132g are taken, are dissolved in 500 milliliters of acetonitriles, potassium carbonate 150g is added, 110g front threes is added portionwise
Base silicon cyanogen, after adding, reaction system is warming up to 70 DEG C of reaction 10h, after reaction terminates, is cooled to room temperature, filters, filtrate decompression
Acetonitrile is reclaimed, residue adds 300 milliliters of toluene, 200 milliliters of 1N NaOH solutions, liquid separation are added in system, and organic layer adds 1N
100 milliliters of NaOH solution, liquid separation, neutrality is washed to, anhydrous magnesium sulfate is dried, filtering, and filtrate decompression recovery solution, residue subtracts
Pressure distills to obtain weak yellow liquid 120g, yield 98%.
The preparation of the 2- thienyls propionitrile (II) of embodiment 2
Take thiophene -2- acetonitrile 123g, dimethyl carbonate 400g, potassium carbonate 300g, TBAB 85g, system heating
To 130 DEG C of reaction 7h, after reaction terminates, system is cooled to room temperature, filtering, the complete carbonic acid diformazan of filtrate decompression recovery unreacted
Ester, residue are evaporated under reduced pressure to colourless liquid 119.19g, yield 87%.
The preparation of the 2- thienyls propionic acid (III) of embodiment 3
Take 2- thienyl propionitrile 137g, 150 milliliters of glacial acetic acid, 49% 200 milliliters of sulfuric acid, system is warming up to 125 DEG C of backflows
6h is reacted, after reaction terminates, system is cooled to room temperature, adds 200 milliliters of water, 300 milliliters of extractions of ethyl acetate, in being washed to
Property, organic layer adjusts pH to 10 with 10%KOH solution, and liquid separation, water layer, 6mol/L hydrochloric acid adjusted to pH to 3,200 milliliters of acetic acid
Ethyl ester is extracted, and anhydrous magnesium sulfate is dried, and filtering, filtrate decompression reclaims to obtain yellow liquid 149g, yield 96%.
The preparation of the Tiaprofenic Acid of embodiment 4 (IV)
2- thienyls propionic acid 156g, zinc acetate 18.3g are taken, at room temperature, chlorobenzoyl chloride 140g is added dropwise, is controlled during dropwise addition
Temperature not heat up too soon, and temperature of reaction system is no more than 40 DEG C, drips off within 50 minutes, and after reaction terminates, system adds 300 milliliters
Ethyl acetate dispersion, 300 milliliters of washings, organic layer anhydrous magnesium sulfate are dried, filtering, filtrate decompression recycling design, residual
The ethyl alcohol recrystallization of thing 70% obtains white crystal 240g, yield 92%, purity 99.21%.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The skill of the industry
For art personnel it should be appreciated that the present invention is not limited to the above embodiments, described in above-described embodiment and specification is explanation
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (5)
- A kind of 1. preparation method of non-steroidal antiphlogiston tiaprofenic acid, it is characterised in that：Using 2- chloromethyl thiophenes as initiation material, Synthesizing thiofuran -2- acetonitriles are reacted with third level natural division, are then methylated with dimethyl carbonate, cyan-hydrolysis, finally and benzene Formyl chloride F-K reaction prepares Tiaprofenic Acid；Specifically comprise the following steps：(1) preparation of thiophene -2- acetonitriles (I)：Using 2- chloromethyl thiophenes and third level natural division as raw material, in polar solvent, Reaction prepares thiophene -2- acetonitriles (I) under alkalescence condition；Specific reaction is as follows：(2) preparation of 2- thienyls propionitrile (II)：Using thiophene -2- acetonitriles and dimethyl carbonate as raw material, urged with alkali and phase transfer Agent catalysis prepares 2- thienyls propionitrile (II)；Specific reaction is as follows：(3) preparation of 2- thienyls propionic acid (III)：Using glacial acetic acid as solvent, the hydrolysis preparation 2- thienyls under the conditions of dilute sulfuric acid Propionic acid (III)；Specific reaction is as follows：(4) preparation of Tiaprofenic Acid (IV)：Using 2- thienyls propionic acid and chlorobenzoyl chloride as raw material, through paying under Louis acid catalysis Gram acylation reaction prepares Tiaprofenic Acid (IV)；Specific reaction is as follows：
- 2. the preparation method of non-steroidal antiphlogiston tiaprofenic acid according to claim 1, it is characterised in that：The step (1) in, polar solvent selection acetonitrile, alkali selection potassium carbonate, reaction temperature is 60-70 DEG C.
- 3. the preparation method of non-steroidal antiphlogiston tiaprofenic acid according to claim 1, it is characterised in that：The step (2) in, alkali selection potassium carbonate, phase transfer catalyst selection TBAB, reaction temperature is 120-130 DEG C.
- 4. the preparation method of non-steroidal antiphlogiston tiaprofenic acid according to claim 1, it is characterised in that：The step (3) in, for dilute sulfuric acid from the dilute sulfuric acid that mass percentage concentration is 49%, reaction temperature is 120-130 DEG C.
- 5. the preparation method of non-steroidal antiphlogiston tiaprofenic acid according to claim 1, it is characterised in that：The step (4) in, lewis acid is zinc acetate, and reaction temperature is room temperature.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659754A (en) * | 2012-05-17 | 2012-09-12 | 东南大学 | Preparation method of tiaprofenic acid |
| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
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- 2017-10-13 CN CN201710954808.7A patent/CN107698554A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659754A (en) * | 2012-05-17 | 2012-09-12 | 东南大学 | Preparation method of tiaprofenic acid |
| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
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Application publication date: 20180216 |